The central theme of this Program Project renewal application elucidates mechanisms by which the ACE2IAng-(1-7)/mas-receptor axis opposes the pressor and growth promoting actions of the ACE/Ang II/A T1 receptor pathway. The proposed research expands upon the original discoveries made by the participating investigators who first established the existence of an internal regulatory mechanism comprising novel proteins of the renin-angiotensin-aldosterone system (RAS) that significantly contribute to the regulation of blood pressure and target organ dysfunction. In this application, the theme of the proposed research continues to pursue the overall hypothesis that hypertension and aging, as well as impired cardiac, renal, vascular and metabolic function, reflect the complex imbalance in the expression of the ACE2IAng-(1- 7)/mas-receptor axis and the ACE/Ang II/A T1 pathway in multiple tissues. New aspects of the research effort emphasize the role of a renin-independent Ang I precursor, Ang-(1-12), novel phosphatase-dependent pathways for Ang-(1-7) actions, nuclear effects of Ang II and Ang-(1-7), a central role of Ang-(1-7) to regulate metabolism via interactions with phosphatase pathways, and novel regulatory pathways of Ang-( 1-7) in pregnancy, The individual focus of the proposed research by the investigators are: Project 1 tests the hypothesis that Ang-( 1-12) constitutes an alternate precursor of angiotensin peptides in the heart and that its regulation and expression from angiotensinogen critically influences the cellular actions of the cardiac RAS: Proiect 2 investigates the hypothesis that Ang-(1-7) counter-regulates the effects of Ang II by up-regulating mitogen-activated protein kinase phosphatases to prevent cardiac hypertrophy and reduce fibrosis; Project 3 evaluates the role of nuclear receptors for Ang II and Ang-(1-7) within the kidney in the context of saltsensitive hypertension and renal injury; Project 4 tests the hypothesis that Ang-(1-7) in the nucleus of the tractus solitarius is necessary for maintaining normal blood pressure, baroreceptor reflex function and metabolism through up-regulation of phosphatases; and Proiect 5 investigates whether Ang-(1-7) acts as a local autocrine/paracrine hormone in the uteroplacental unit regulating prostanoids during early and late normotensive and hypertensive pregnancy. Four Cores (Administration and Biostatics, Celfular and Molecular Biology, Biochemistry, and Animal Resouroe) provide strong support to facilitate the integrative effort.:of the investigators, such that the sharing of research tools and techniques allows the development of multi-faceted approach to facilitate the successful completion of the proposed studies. Cardiovascular disease remains the most deadly disease among industrialized countries. The ongoing effort of the proposed research seeks to understand the mechanisms that contribute to the regulation of an important hormonal system - the renin angiotensin system in multiple tissues including the brain, heart, kidney and uterus/placenta. Understanding the regulation of this system is vital to the prevention of cardiovascular disease as well as in the design of effective therapies to reduce the consequences of the disease.